Treatment of leptomeningeal metastases in a rat model using a recombinant adenovirus containing the HSV-tk gene

Vincent, Audrey; Esandi, Maria del C.; Someren, GD van; Noteboom, J.L.; Avezaat, C. J. J.; Vecht, C. J.; Smitt, Peter A. Sillevis; Bekkum, D. W. van; Valerio, D.; Pm, Hoogerbrugge; Bout, A.

doi:10.3171/jns.1996.85.4.0648

Cited by 21 publications

(6 citation statements)

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“…Our results could have implications for leptomeningeal tumors and tumors metastasizing to the brain from primary lung, breast, and melanoma cancers, [65][66][67] as well as tumors that often disseminate through the cerebrospinal fluid (CSF), such as those seen in pediatric medulloblastoma. 68 Novel strategies for these cancers have utilized replication-deficient adenovirus, 69,70 replication-competent reovirus, 68,71 herpes simplex virus, [6][7][8][9][10]72 and immunotoxin 73 approaches to slow but not eliminate tumor growth at therapeutically efficacious levels. Only the use of a replication-competent herpes simplex virus vector resulted in long-term survival in a 9L model of disseminated glioma.…”

Section: Discussionmentioning

confidence: 99%

Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model

et al. 2008

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The disseminated characteristics of human glioblastoma multiforme (GBM) make it a particularly difficult tumor to treat with long-term efficacy. Most preclinical models of GBM involve treatment of a single tumor mass. For therapeutic outcomes to translate from the preclinical to the clinical setting, induction of an antitumor response capable of eliminating multifocal disease is essential. We tested the hypothesis that expression of Flt3L (human soluble FMS-like tyrosine kinase 3 ligand) and TK (herpes simplex virus type 1-thymidine kinase) within brain gliomas would mediate regression of the primary, treated tumor mass and a secondary, untreated tumor growing at a distant site from the primary tumor and the site of therapeutic vector injection. In both the single-GBM and multifocal-GBM models used, all saline-treated control animals succumbed to tumors by day 22. Around 70% of the animals bearing a single GBM mass treated with an adenovirus expressing Flt3L (AdFlt3L) and an adenovirus expressing TK (AdTK + GCV) survived long term. Approximately 50% of animals bearing a large primary GBM that were implanted with a second GBM in the contralateral hemisphere at the same time the primary tumors were being treated with AdFlt3L and AdTK also survived long term. A second multifocal GBM model, in which bilateral GBMs were implanted simultaneously and only the right tumor mass was treated with AdFlt3L and AdTK, also demonstrated long-term survival. While no significant difference in survival was found between unifocal and multifocal GBM-bearing animals treated with AdFlt3L and AdTK, both treatments were statistically different from the saline-treated control group (p < 0.05). Our results demonstrate that combination therapy with AdFlt3L and AdTK can eradicate multifocal brain tumor disease in a syngeneic, intracranial GBM model.

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Section: Discussionmentioning

confidence: 99%

Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model

et al. 2008

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“…84,85 Other Agents: Agents under investigation include dacarbazine, 86 nitrosoureas, 87 busulfan, 88,89 trimetrexate, 90 melphalan, 91 topotecan, 92 immunotherapy with lymphokine-activated killer cells and interleukin-2, [93][94][95] and gene therapy. 61,96 IT IL-2 has been predominantly studied in patients with leptomeningeal disease from disseminated melanoma. In one preliminary report, 12 of 46 patients showed a response to IT IL-2 (1.2 million units daily for 5 days, then 2 to 3 times weekly as tolerated), with 2 still alive beyond 32 and 90 months, respectively.…”

Section: Emerging Therapiesmentioning

confidence: 99%

Leptomeningeal Metastases: Current Concepts and Management Guidelines

Chowdhary

Chamberlain

2005

J Natl Compr Canc Netw

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Neoplastic infiltration of the meninges occurs when malignant cells gain entry into the cerebrospinal fluid (CSF). This is clinically recognized in 4% to 7% of all cancer patients. Leptomeningeal metastases may involve any part of the neural axis via tumor seeding; thus, a multitude of clinical presentations involving one or more domains exist, including the cerebral hemisphere, cranial nerves, and spinal cord and roots. The diagnosis of CSF metastases is often delayed and not appreciated until fixed neurologic deficits become evident. Adequate cytologic analysis of CSF fluid, neuroradiography of brain and spine, and an appropriate clinical context are the key element in diagnosing leptomeningeal metastases. A major challenge of treating neoplastic meningitis is the importance of treating the entire neural axis and stratifying patients in poor risk or good risk categories. Treatment is palliative and involves stabilizing neurologic status and prolonging survival. Median survival for untreated patients is 4 to 6 weeks. Treatment in a broad perspective entails radiotherapy and chemotherapy (systemic and intra-CSF). Commonly used intra-CSF chemotherapy regimens use drugs such as methotrexate, cytarabine, thiotepa, and a sustained-release liposome-encapsulated form of cytarabine (Depocyt, SkyePharma, London, UK). Patients with neoplastic meningitis usually experience a limited survival, even when treated using close adherence to evaluation algorithms and treatment protocols. In randomized controlled clinical trials using currently available intra-CSF chemotherapeutic agents, median survival in carefully selected, study-eligible groups of patients was 2 to 6 months.

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“…• Radiolabeled and toxin-linked monoclonal antibody treatment approaches are under investigation for patients with both solid tumor and lymphomatous meningitis [49,50]. • Other agents currently under investigation include diazoquinone [51], dacarbazine [52], ACNU [53], trimetrexate [54], melphalan [55], MCNU [56], topotecan [57], busulfan [58], mafosfamide [59], lymphokine-activated killer cells and Il-2 [60,61], Au-colloid [62], and gene therapy [63].…”

Section: Radiation Therapymentioning

confidence: 99%

Neoplastic meningitis

Kim

Glantz

2001

Curr. Treat. Options in Oncol.

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Neoplastic meningitis is recognized clinically in 4% to 7% of patients with extraneural cancer, but it remains dramatically under-diagnosed. The frequency of neoplastic meningitis is increasing because of heightened clinical suspicion, improved neuroimaging techniques, and longer survival in patients with extraneural cancer Longer survival allows residual tumor cells within central nervous system sanctuary sites time to become symptomatic. Affected patients may present with cerebral, cranial nerve, or spinal signs and symptoms, depending on the specific sites of central nervous system (CNS) involvement. Magnetic Resonance Imaging (MRI) seems to be sensitive for detecting metastatic deposits along the neuraxis. However, metastases at a microscopic level are below the resolution of MRI scanning. As a result, the standard diagnostic test for neoplastic meningitis remains the cytologic identification of malignant cells in cerebrospinal fluid (CSF). Although CSF cytology is useful, malignant cells are not detected in as many as one third of patients who have compelling clinical or radiographic evidence of neoplastic meningitis. Novel assays are being tested that may enhance the early identification of malignant cells in CSF. Currently, the diagnosis occurs generally after the onset of neurologic manifestations and heralds a rapidly fatal course for most patients. By the time symptoms appear, most tumors have disseminated widely within the CNS, due to cortical irritation, compression of nervous system structures, or obstruction of CSF flow. At this stage surgery, cranial irradiation, and chemotherapy are rarely, if ever, curative. The goals of treatment are to improve or to stabilize the neurologic status of patients and to prolong survival. A major problem in treating neoplastic meningitis is that the entire neuraxis must be treated. If only symptomatic areas are treated, reseeding of the neuraxis with tumor cells will occur. Therefore, intrathecal chemotherapy remains a mainstay of therapy. Currently, four therapeutic agents are available for intrathecal treatment: methotrexate, ara-C, sustained-release ara-C (DepoCyt; Chiron Therapeutics, San Francisco, CA), and thiotepa. Unfortunately, intrathecal chemotherapy does not treat bulky disease in the subarachnoid space, and often is slow to stabilize progressive neurologic deficits. For these reasons, radiation therapy to sites of symptomatic disease and sites of bulky disease on imaging studies is recommended. High dose intravenous methotrexate may be as effective as intrathecal methotrexate. Alternative approaches (which offer less toxicity, enhanced therapeutic effect, and prolonged survival) are being investigated.

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Treatment of leptomeningeal metastases in a rat model using a recombinant adenovirus containing the HSV-tk gene

Cited by 21 publications

References 21 publications

Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model

Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model

Leptomeningeal Metastases: Current Concepts and Management Guidelines

Neoplastic meningitis

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